US5234956A - Method of preventing NMDA receptor complex-mediated neuronal damage - Google Patents

Method of preventing NMDA receptor complex-mediated neuronal damage Download PDF

Info

Publication number
US5234956A
US5234956A US07/949,342 US94934292A US5234956A US 5234956 A US5234956 A US 5234956A US 94934292 A US94934292 A US 94934292A US 5234956 A US5234956 A US 5234956A
Authority
US
United States
Prior art keywords
nmda
nitroprusside
disease
nitroglycerin
human
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US07/949,342
Other languages
English (en)
Inventor
Stuart A. Lipton
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Childrens Medical Center Corp
Original Assignee
Childrens Medical Center Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Childrens Medical Center Corp filed Critical Childrens Medical Center Corp
Priority to US07/949,342 priority Critical patent/US5234956A/en
Priority to US08/006,326 priority patent/US5506231A/en
Priority to US08/025,028 priority patent/US5455279A/en
Application granted granted Critical
Publication of US5234956A publication Critical patent/US5234956A/en
Priority to DK93923724T priority patent/DK0661973T3/da
Priority to AU53481/94A priority patent/AU5348194A/en
Priority to AT93923724T priority patent/ATE330606T1/de
Priority to DE69334035T priority patent/DE69334035T2/de
Priority to ES93923724T priority patent/ES2264122T3/es
Priority to EP93923724A priority patent/EP0661973B1/en
Priority to PCT/US1993/009019 priority patent/WO1994006428A1/en
Priority to US08/407,973 priority patent/US5747545A/en
Priority to US08/482,365 priority patent/US5801203A/en
Priority to US09/138,580 priority patent/US6071876A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/28—Compounds containing heavy metals
    • A61K31/295—Iron group metal compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A61P25/10—Antiepileptics; Anticonvulsants for petit-mal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • This invention relates to the treatment of nervous system disorders, particularly disorders mediated by the N-methyl-D-aspartate (NMDA) subtype of excitatory amino acid receptor complex.
  • NMDA N-methyl-D-aspartate
  • Glutamate has been implicated as a significant factor in the neurotoxicity associated with hypoxic-ischemic encephalopathy, anoxia, hypoglycemia, seizures, trauma, and several degenerative neurological disorders such as the AIDS dementia complex and other neurological manifestations of AIDS, Huntington's disease and Parkinsonism (Hahn et al., Proc. Natl. Acad. Sci. USA 85:6556, 1988; Choi, Neuron 1:623, 1988; Rothman et al., Trends Neurosci. 10:299, 1987; Meldrum et al., Trends Pharm. Sci. 11:379, 1990).
  • one aspect of the invention features a method for reducing NMDA receptor complex-mediated neuronal damage in a mammal, by administering one of the above-described compounds to the mammal.
  • oxidation of the NMDA receptor is known to protect against NMDA receptor-mediated neuronal damage (see, e.g., PCT W091/02180). It is also known that the active species of nitroglycerin and nitroprusside is nitric oxide (NO) (see, e.g., Garthwaite et al. (Trends in Neurosciences 14:60, 1991). Accordingly, one possible mechanism for the protective effect that I have discovered is nitric oxide-induced oxidation of the NMDA receptor-channel complex.
  • NO nitric oxide
  • a second aspect of the invention features a method for reducing NMDA receptor complex-mediated neuronal damage by administering a nitric-oxide generating compound, in a concentration effective to cause such reduction.
  • This second aspect of the invention is founded on the premise that NO acts on the NMDA receptor-channel complex to protect against NMDA receptor-mediated damage.
  • the mammal is a human infected with a virus affecting the nervous system--e.g., measles or human immunodeficiency virus (HIV); and the human manifests symptoms of the AIDS related complex or acquired immunodeficiency syndrome.
  • a virus affecting the nervous system e.g., measles or human immunodeficiency virus (HIV); and the human manifests symptoms of the AIDS related complex or acquired immunodeficiency syndrome.
  • the mammal has a disorder such as hypoxia, ischemia, hypoglycemia, trauma, seizures or stroke, or is likely to become subject to these, i.e., could be treated prophylactically.
  • NMDA receptor-mediated neuronal damage any neuronal injury which results from stimulation or costimulation of the NMDA receptor-channel complex, a receptor-channel complex which is found on a subset of mammalian neurons and which includes a molecule that interacts with NMDA or similar agonists (see below) to induce neuron excitation.
  • nitric oxide-generating compound any compound which produces a sufficient amount of nitric oxide upon administration to a mammal to reduce neuronal damage or injury.
  • Useful compounds of the second aspect of the instant invention include any nitric oxide-generating compounds. Verification that a particular compound provides protective oxidation of the NMDA receptor itself is step well understood by those skilled in the art (see, e.g., PCT WO 91/02810). Moreover, applicant notes that the literature describes the enzyme, NO synthase, which produces nitric oxide in certain cell types; this enzyme and its role in neuronal function is discussed in, e.g., Garthwaite et al. (Trends in Neurosciences 14:60, 1991) and Hope et al. (Proc. Natl. Acad. Sci. USA 88:2811, 1991).
  • the two preferred compounds of the first aspect of the invention i.e., nitroglycerin and nitroprusside
  • provide the advantage of a proven record of safe human administration i.e., for treatment for cardiovascular disorders.
  • Disorders which may be treated by the method of the invention include hypoxia, ischemia, hypoglycemia, trauma, seizures, stroke, AIDS dementia and other neurological manifestations of HIV (see, e.g., U.S. Ser. No. 571,949) or other viruses affecting the nervous system, and, generally, acute and chronic neurodegenerative disorders, including, but not limited to Parkinson's disease, Alzheimer's disease, and Huntington's disease .
  • the ability of NO to be transported and to cross cell membranes facilitates therapies according to the invention.
  • FIG. 1 is a bar graph showing that nitroprusside prevents NMDA-mediated neurotoxicity.
  • FIG. 2 is a bar graph of intracellular Ca 2+ concentration (i.e., [Ca 2+ ]i) in (a) control cells and in the presence of (b) NMDA alone, (c) NMDA after dithiothreitol (DTT), and (d) NMDA after DTT and nitroprusside.
  • NMDA intracellular Ca 2+ concentration
  • the present invention is based on the finding that the compounds nitroprusside and nitroglycerin reduce NMDA receptor complex-mediated neuronal damage (see below). This reduction in damage may be due to oxidation of the NMDA receptor at the redox modulatory site. The reduction is associated with a decrease in NMDA receptor-operated channel activation by excitatory amino acids (such as NMDA) and a concomitant decrease in intracellular calcium leading to neurotoxicity.
  • excitatory amino acids such as NMDA
  • glutamate-related compounds An increased level of one or more glutamate-related compounds is associated with many neurodegenerative disorders (e.g., those listed above).
  • neuronal injury may result from stimulation of the NMDA receptor-channel complex by other excitatory amino acids, such as aspartate, quinolinate, homocysteic acid, cysteine sulphinic acid, or cysteic acid, or from stimulation by excitatory peptides, such as N-acetyl aspartyl glutamate.
  • Nitroglycerin (1,2,3-propanetriol trinitrate or glyceryl trinitrate or GTN), nitroprusside and NO-generating derivatives of either one of those compounds are considered to be particularly useful in the invention.
  • Compounds of the second aspect of the invention may be tested for efficacy in reducing neuronal damage using the assays described below--i.e. in assays of NMDA evoked ionic current (see, e.g., PCT WO 91/02810), in assays of NMDA-evoked increases in intracellular Ca 2+ (see below), or in assays of neuronal cell death (see below).
  • An effective compound will cause a decrease in ionic current, intracellular Ca 2+ concentration, or in neuronal cell death, respectively.
  • Compounds most preferred in the invention are those which effect the greatest protection of neurons from NMDA receptor complex-mediated injury e.g., that injury resulting from stimulation of the NMDA receptor by NMDA(as shown below) or other excitatory amino acids or stimulation by excitatory peptides, such as N-acetyl aspartyl glutamate.
  • Neonatal cortical neurons were prepared according to the general method of Snodgrass et al. (1980) Brain Res. 190:123-138; and Rosenberg et al (1988) J. Neurosci. 8:2887-2899. Cultures are monitored following a brief exposure (5 minutes) to 100 ⁇ M NMDA, or to 5 mM DTT (for 5 minutes) followed by 100 ⁇ M NMDA (for 5 additional minutes), and overnight incubation (i.e., 16 to 24 hours).
  • a compound may be tested for utility in the method of the invention using any type of neuronal cell from the central nervous system, as long as the cell can be isolated intact by conventional techniques.
  • cortical neuron cultures are used above, retinal ganglion cell neurons, spinal cord neurons, cerebellar granular neurons, or any neuron containing NMDA receptors (e.g., neurons from other regions of the cortex) may also be used. Such neurons may be prenatal or postnatal.
  • the compound nitroprusside was tested for its ability to increase survival of neonatal cortical neurons.
  • the neuronal cells were incubated for 16-24 hours at 37° C. in a humidified atmosphere of 5% CO 2 and 95% air.
  • An analysis of variance was used to test for significance; this analysis was followed by a Sheffe test for multiple comparison of means (Hahn et al., 1988, supra). Doses of nitroprusside as low as 0.1 nM are expected to have neuroprotective effects.
  • the concentration of intracellular free Ca 2+ ([Ca 2+ ]i) is measured in neonatal cortical neurons by digital imaging microscopy with the Ca 2+ sensitive fluorescent dye fura 2 as follows. The same cortical neuronal cultures as described above are used.
  • the fluid bathing the neurons consists of Hanks' balanced salts: 137.6 mM NaCl, 1 mM NaHCO 3 , 0.34 mM Na 2 HPO 4 , 0.44 mM KH 2 PO 4 , 5.36 mM KCl, 1.25 mM CaCl 2 , 0.5 mM MgSO 4 , 0.5 mM MgCl 2 , 5 mM Hepes NaOH, 22.2 mM glucose, and phenol red indicator (0.001% v/v); pH 7.2.
  • NMDA and other substances are usually applied to the neurons by pressure ejection after dilution in this bath solution.
  • Neuronal [Ca 2+ ]i is analyzed with fura 2-acetoxy-methyl ester (AM) as described [Grynkiewicz, et al., J. Biol. Chem. 260:3440 (1985); Williams et al., Nature 318:558 (1985); Connor et al., J. Neurosci. 7:1384 (1987); Connor et al., Science 240:649 (1988); Cohan et al., J. Neurosci. 7:3588 (1987); Mattson, et al., ibid, 9:3728 (1989)]. After adding Eagle's minimum essential medium containing 10 ⁇ M fura 2-AM to the neurons, the cultures are incubated at 37° C.
  • the cells are incubated in a solution of Hepes-buffered saline with Hanks' balanced salts.
  • the [Ca 2+ ]i is calculated from ratio images that are obtained by measuring the fluorescence at 500 nm that is excited by 350 and 380 nm light with a DAGE MTI 66 SIT or QUANTEX QX-100 Intensified CCD camera mounted on a Zeiss Axiovert 35 microscope. Exposure time for each picture is 500 ms. Analysis is performed with a Quantex (Sunnyvale, Calif.) QX7-210 image-processing system. Since cells are exposed to ultraviolet light only during data collection (generally less than a total of 20 s per cell), bleaching of fura 2 is minimal.
  • NMDA-receptor mediated neurotoxicity has been shown to involve an increase in intracellular Ca 2+ concentration.
  • the increase in [Ca 2+ ]i was documented in the following experiment. Intracellular Ca 2+ was measured as described above.
  • Application of 10 ⁇ M NMDA produced a striking increase in [Ca 2+ ]i [FIG. 2, columns 2-5(b)].
  • levels following NMDA addition increased to 200 nM.
  • Verification that the effect at issue involves the NMDA redox site can be provided as follows.
  • a maximal chemical oxidation with DTNB abrogates the effect of nitroprusside, strongly suggesting that nitroprusside is acting in the same manner under these conditions (i.e., as an oxidizing agent) because it has no further effect after DTNB oxidation of the redox modulatory site of the NMDA receptor-channel complex. It should be noted that once the redox modulatory site is oxidized or reduced, even after subsequent wash out of the redox agent, the site remains in this state until another effective redox agent is introduced.
  • compounds of the invention may be administered by any of a number of routes in an amount sufficient to attenuate an NMDA-evoked ionic current or a rise in [Ca 2+ ]i, or neurotoxicity.
  • the compound may be included in a pharmaceutical preparation, using a pharmaceutical carrier (e.g., physiological saline); the exact formulation of the therapeutic mixture depends upon the route of administration.
  • a pharmaceutical carrier e.g., physiological saline
  • the compound is administered orally or intravenously, but it may also be administered sublingually, by spray, by transdermal patch, or by ointment.
  • nitroglycerine or their derivatives including all those preparations commercially available, e.g., those listed in the Physician's Desk Reference (1991) under coronary vasodilators or under nitroglycerin or nitroglycerin intravenous and including isosorbide mononitrate, isosorbide dinitrate, nitroglycerin sublingual, NT-1, Niotrocor, Nitroderm, Nitrodisc, Nitro-dur, Nitro-Dur II, Nitrofilm, Nitrogard, Nitroglin, Nitropen, Tridil, and 6-chloro-2-pyridylmethyl nitrate) are administered at 0.01-1000 mg/day, in divided doses.
  • nitric oxide-generating compounds determined to be an effective neuroprotective agent by the assays described herein, is administered orally, intravenously, sublingually, by spray, or by transdermal patch or ointment at a dosage suitable to reduce neuronal damage, or NMDA evoked ionic current or increased [Ca 2+ ]i.
  • such compounds are administered in dosages of 0.1-5 mg/day in divided doses.
  • the compounds of the invention can be utilized to protect against a number of neurotoxic disorders caused by elevated levels of glutamate or related compounds. Such neurotoxic disorders include ischemia, hypoxia, hypoglycemia, trauma, epilepsy, Huntington's disease, and Alzheimer's disease and other neurodegenerative disorders.
  • the method of the invention is particularly preferred for the treatment of AIDS dementia and other neurological manifestations of the AIDS virus. The method may also be used for reduction of neuronal damage resulting from infection with other viruses which cause damage to the nervous system.
  • the method described herein is useful for reducing neuronal injury in any mammal having NMDA receptors. Treatment of neuronal damage in humans is the preferred utility; but the method may also be employed successfully for veterinary purposes.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Immunology (AREA)
  • Virology (AREA)
  • Emergency Medicine (AREA)
  • Dermatology (AREA)
  • Diabetes (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Psychology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Pain & Pain Management (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • AIDS & HIV (AREA)
  • Toxicology (AREA)
  • Vascular Medicine (AREA)
  • Obesity (AREA)
  • Molecular Biology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Endocrinology (AREA)
US07/949,342 1989-03-31 1992-09-22 Method of preventing NMDA receptor complex-mediated neuronal damage Expired - Lifetime US5234956A (en)

Priority Applications (13)

Application Number Priority Date Filing Date Title
US07/949,342 US5234956A (en) 1991-04-19 1992-09-22 Method of preventing NMDA receptor complex-mediated neuronal damage
US08/006,326 US5506231A (en) 1989-03-31 1993-01-21 Treatment of aids dementia, myelopathy and blindness
US08/025,028 US5455279A (en) 1991-04-19 1993-03-02 Regimen method of mediating neuronal damage using nitroglycerine
PCT/US1993/009019 WO1994006428A1 (en) 1992-09-22 1993-09-22 Method of preventing nmda receptor complex-mediated neuronal damage
AT93923724T ATE330606T1 (de) 1992-09-22 1993-09-22 Verfahren zur vorbeugung von nmda-rezeptor vermittelten neuronalen schäden
AU53481/94A AU5348194A (en) 1992-09-22 1993-09-22 Method of preventing nmda receptor complex-mediated neuronal damage
DK93923724T DK0661973T3 (da) 1992-09-22 1993-09-22 Fremgangsmåde til forebyggelse af NMDA-receptorkompleksmedieret neuronskade
DE69334035T DE69334035T2 (de) 1992-09-22 1993-09-22 Verfahren zur vorbeugung von nmda-rezeptor vermittelten neuronalen schäden
ES93923724T ES2264122T3 (es) 1992-09-22 1993-09-22 Metodo para la prevencion de deterioros neuronales inducidos por el complejo receptor nmda.
EP93923724A EP0661973B1 (en) 1992-09-22 1993-09-22 Method of preventing nmda receptor complex-mediated neuronal damage
US08/407,973 US5747545A (en) 1991-04-04 1995-03-22 Method of preventing NMDA receptor complex-mediated Neuronal damage
US08/482,365 US5801203A (en) 1991-04-19 1995-06-07 Nitroglycerine patch
US09/138,580 US6071876A (en) 1991-04-19 1998-08-21 Method of preventing NMDA receptor complex-mediated neuronal damage

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US68896591A 1991-04-19 1991-04-19
US07/949,342 US5234956A (en) 1991-04-19 1992-09-22 Method of preventing NMDA receptor complex-mediated neuronal damage

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US68896591A Continuation 1989-03-31 1991-04-19

Related Child Applications (3)

Application Number Title Priority Date Filing Date
US08/006,326 Continuation-In-Part US5506231A (en) 1989-03-31 1993-01-21 Treatment of aids dementia, myelopathy and blindness
US08/025,028 Continuation-In-Part US5455279A (en) 1991-04-04 1993-03-02 Regimen method of mediating neuronal damage using nitroglycerine
US08/482,365 Continuation-In-Part US5801203A (en) 1991-04-19 1995-06-07 Nitroglycerine patch

Publications (1)

Publication Number Publication Date
US5234956A true US5234956A (en) 1993-08-10

Family

ID=24766524

Family Applications (1)

Application Number Title Priority Date Filing Date
US07/949,342 Expired - Lifetime US5234956A (en) 1989-03-31 1992-09-22 Method of preventing NMDA receptor complex-mediated neuronal damage

Country Status (7)

Country Link
US (1) US5234956A (es)
EP (1) EP0581856B1 (es)
JP (2) JPH06506690A (es)
AT (1) ATE182076T1 (es)
DE (1) DE69229598T2 (es)
ES (1) ES2134804T3 (es)
WO (1) WO1992018112A1 (es)

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0661973A1 (en) * 1992-09-22 1995-07-12 The Children's Medical Center Corporation Method of preventing nmda receptor complex-mediated neuronal damage
US5475007A (en) * 1993-05-28 1995-12-12 The Regents Of The University Of California 1,2,3,4-tetrahydroquinoline-2,3,4-trione-3 or 4-oximes and the use thereof
US5648101A (en) * 1994-11-14 1997-07-15 Tawashi; Rashad Drug delivery of nitric oxide
US5650442A (en) * 1993-10-08 1997-07-22 The United States Of America As Represented By The Department Of Health And Human Services Use of nitric oxide releasing compounds as hypoxic cell radiation sensitizers
US5691423A (en) * 1992-08-24 1997-11-25 The United States Of America As Represented By The Department Of Health And Human Services Polysaccharide-bound nitric oxide-nucleophile adducts
US5714511A (en) * 1995-07-31 1998-02-03 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Selective prevention of organ injury in sepsis and shock using selection release of nitric oxide in vulnerable organs
US5721365A (en) * 1989-09-15 1998-02-24 Us Health N-substituted piperazine NONOates
US5731305A (en) * 1989-09-15 1998-03-24 The United States Of America As Represented By The Department Of Health And Human Services Anti-hypertension compositions of secondary amine-nitric oxide adducts and use thereof
US5840759A (en) * 1993-10-08 1998-11-24 The United States Of America As Represented By The Department Of Health And Human Services Use of nitric oxide releasing compounds to protect noncancerous cells from chemotherapeutic agents
US5910316A (en) * 1992-08-24 1999-06-08 The United States Of America, As Represented By The Department Of Health And Human Services Use of nitric oxide-releasing agents to treat impotency
EP0951293A1 (en) * 1996-11-06 1999-10-27 Bristol-Myers Squibb Company Method for treating alzheimer's disease
US6071876A (en) * 1991-04-19 2000-06-06 Children's Medical Center Corporation Method of preventing NMDA receptor complex-mediated neuronal damage
EP1050309A1 (en) * 1998-01-30 2000-11-08 Sumitomo Pharmaceuticals Company, Limited Neurotrophic factor secretion promoters
US6310052B1 (en) 1996-06-04 2001-10-30 Queen's University At Kingston Nitrate esters and their use for neurological conditions
US6451337B1 (en) 1998-11-25 2002-09-17 The University Of Akron Chitosan-based nitric oxide donor compositions
US20040110691A1 (en) * 2001-11-13 2004-06-10 Stamler Jonathan S. Thiol reactive agents as a therapeutic modality
US20050137191A1 (en) * 1996-06-04 2005-06-23 Thatcher Gregory R. Nitrate esters and their use for mitigating cellular damage
US7326730B2 (en) 2000-02-22 2008-02-05 Adamas Pharmaceuticals, Inc. Aminoadamantane derivatives as therapeutic agents
EP2111858A1 (en) 2008-04-25 2009-10-28 EPFL Ecole Polytechnique Fédérale de Lausanne Novel treatment for alzheimer's disease
WO2009152483A2 (en) * 2008-06-12 2009-12-17 University Of Alabama Huntsville Nitric oxide induced adaptive resistance as a therapy for central nervous system diseases and trauma
WO2009152479A1 (en) * 2008-06-12 2009-12-17 University Of Alabama Huntsville Compositions comprising nitric oxide or nitric oxide donors for the treatment of neurodegenerative diseases of trauma
EP2289489A2 (en) 2003-11-05 2011-03-02 Merz Pharma GmbH & Co. KGaA Compositions comprising cyclohexylamines and aminoadamantanes
EP2397122A2 (en) 2004-06-17 2011-12-21 Merz Pharma GmbH & Co. KGaA Formulations of neramexane dosage forms
US8901171B2 (en) 2010-01-27 2014-12-02 Takeda Pharmaceutical Company Limited Compounds for suppressing a peripheral nerve disorder induced by an anti-cancer agent
US9364521B2 (en) 2012-06-04 2016-06-14 Diamedica Inc. Human tissue kallikrein 1 glycosylation isoforms
US9616015B2 (en) 2012-05-25 2017-04-11 Diamedica Inc. Formulations of human tissue kallikrein-1 for parenteral delivery and related methods
US11857608B2 (en) 2017-03-09 2024-01-02 Diamedica Inc. Dosage forms of tissue kallikrein 1

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5385940A (en) * 1992-11-05 1995-01-31 The General Hospital Corporation Treatment of stroke with nitric-oxide releasing compounds
JP3560609B2 (ja) * 1992-11-13 2004-09-02 イミュネックス・コーポレーション Ｅｌｋリガンドと呼ばれる新規なサイトカイン
DE4305881C1 (de) * 1993-02-26 1994-03-03 Lohmann Therapie Syst Lts Transdermales therapeutisches System mit Wirkstoffen, welche Stichoxid-Quellen darstellen, Verfahren zu seiner Herstellung sowie seine Verwendung
US6303769B1 (en) 1994-07-08 2001-10-16 Immunex Corporation Lerk-5 dna
US6066333A (en) * 1994-09-22 2000-05-23 William Harvey Research Limited Pharmaceutical control of inflammation
CA2132690A1 (en) * 1994-09-22 1996-03-23 Dean Willis Control and modulation of inflammatory response in humans in need of such control and modulation
GB0007193D0 (en) * 2000-03-25 2000-05-17 Univ Manchester Treatment of movrmrnt disorders

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4806543A (en) * 1986-11-25 1989-02-21 Board Of Trustees Of The Leland Stanford Junior University Method and compositions for reducing neurotoxic injury
WO1991002810A1 (en) * 1989-08-09 1991-03-07 The Children's Medical Center Corporation Nmda oxidizing agents for protecting neurons from injury
US5091391A (en) * 1990-08-16 1992-02-25 University Of Pittsburgh Of The Commonwealth System Of Higher Education Method of resisting neurodegenerative disorders

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4806543A (en) * 1986-11-25 1989-02-21 Board Of Trustees Of The Leland Stanford Junior University Method and compositions for reducing neurotoxic injury
WO1991002810A1 (en) * 1989-08-09 1991-03-07 The Children's Medical Center Corporation Nmda oxidizing agents for protecting neurons from injury
US5091391A (en) * 1990-08-16 1992-02-25 University Of Pittsburgh Of The Commonwealth System Of Higher Education Method of resisting neurodegenerative disorders

Non-Patent Citations (39)

* Cited by examiner, † Cited by third party
Title
Aizenman et al., Neuron 2:1257 1263, 1989. *
Aizenman et al., Neuron 2:1257-1263, 1989.
Aizenman et al., Neuron 5:8411 846, 1990. *
Aizenman et al., Neuron 5:8411-846, 1990.
Choi et al., J. Pharmacol. and Exp. Therapeutics 242:713 730, 1987. *
Choi et al., J. Pharmacol. and Exp. Therapeutics 242:713-730, 1987.
Choi, Neuron. 1:623, 1988. *
Davenport et al., Eur. J. Pharm. 154:73 78, 1988. *
Davenport et al., Eur. J. Pharm. 154:73-78, 1988.
Garthwaite et al., Neuroscience, vol. 26, No. 1, pp. 321 326, 1988. *
Garthwaite et al., Neuroscience, vol. 26, No. 1, pp. 321-326, 1988.
Garthwaite et al., Trends in Neurosciences 14:60, 1991. *
Garthwaite, Trends in Pharmacological Sciences, vol. 14, No. 2, pp. 60 67, 1991. *
Garthwaite, Trends in Pharmacological Sciences, vol. 14, No. 2, pp. 60-67, 1991.
Goldberg et al., J. Pharm. Exp. Therapeutics 245:1081 1087, 1988. *
Goldberg et al., J. Pharm. Exp. Therapeutics 245:1081-1087, 1988.
Hahn et al., Proc. Natl. Acad. Sci. USA 85:6556 6560, 1988. *
Hahn et al., Proc. Natl. Acad. Sci. USA 85:6556-6560, 1988.
Hope et al., Proc. Natl. Acad. Sci. USA 88:2811, 1991. *
Hope et al., Proc. Natl. Acad. Sci. USA, vol. 88, pp. 2811 2814, Apr. 1991. *
Hope et al., Proc. Natl. Acad. Sci. USA, vol. 88, pp. 2811-2814, Apr. 1991.
Levy et al., Neurosci. Letters 110:291 296, 1990. *
Levy et al., Neurosci. Letters 110:291-296, 1990.
Majewska et al., Brain Res. 537:328 332, 1990. *
Majewska et al., Brain Res. 537:328-332, 1990.
Meldrum et al., Trends in Pharmacological Sciences, vol. 11, pp. 379 387, Sep. 1990. *
Meldrum et al., Trends in Pharmacological Sciences, vol. 11, pp. 379-387, Sep. 1990.
Meldrum et al., Trends Pharm. Sci. 11:379, 1990. *
Merck Index, 9th Edition, pp. 858 859, 6429 and 6429, 1976. *
Merck Index, 9th Edition, pp. 858-859, #6429 and #6429, 1976.
Merck Index, p. 858. *
Rothman et al., Trends Neurosci. 10:299, 1987. *
Sernagor, Neuron. 2:1221 1227, 1989. *
Sernagor, Neuron. 2:1221-1227, 1989.
Seubert, Brain Research 492:366 370, 1990. *
Seubert, Brain Research 492:366-370, 1990.
Sucher et al., Neuropharmacology and Neurotoxicity 1:29 32, 1990. *
Sucher et al., Neuropharmacology and Neurotoxicity 1:29-32, 1990.
Weiss et al., Science 247:1474, 1990. *

Cited By (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5731305A (en) * 1989-09-15 1998-03-24 The United States Of America As Represented By The Department Of Health And Human Services Anti-hypertension compositions of secondary amine-nitric oxide adducts and use thereof
US5721365A (en) * 1989-09-15 1998-02-24 Us Health N-substituted piperazine NONOates
US6071876A (en) * 1991-04-19 2000-06-06 Children's Medical Center Corporation Method of preventing NMDA receptor complex-mediated neuronal damage
US6290981B1 (en) 1992-08-24 2001-09-18 The United States Of America As Represented By The Department Of Health And Human Services Use of nitric oxide-releasing agents to treat impotency
US5691423A (en) * 1992-08-24 1997-11-25 The United States Of America As Represented By The Department Of Health And Human Services Polysaccharide-bound nitric oxide-nucleophile adducts
US5910316A (en) * 1992-08-24 1999-06-08 The United States Of America, As Represented By The Department Of Health And Human Services Use of nitric oxide-releasing agents to treat impotency
EP0661973A4 (en) * 1992-09-22 1999-12-22 Childrens Medical Center METHOD FOR PREVENTING NEURONAL DETERIORATIONS INDUCED BY THE NMDA RECEPTOR COMPLEX.
EP0661973A1 (en) * 1992-09-22 1995-07-12 The Children's Medical Center Corporation Method of preventing nmda receptor complex-mediated neuronal damage
US5652368A (en) * 1993-05-28 1997-07-29 The Regents Of The University Of California 1,2,3,4-tetrahydroquinoline 2,3,4-trione-3 or 4-oximes
US5475007A (en) * 1993-05-28 1995-12-12 The Regents Of The University Of California 1,2,3,4-tetrahydroquinoline-2,3,4-trione-3 or 4-oximes and the use thereof
US5837736A (en) * 1993-10-08 1998-11-17 The United States Of America As Represented By The Department Of Health And Human Services Nitric oxide-releasing compounds to sensitive cancerous cells to chemotherapeutic agents
US5840759A (en) * 1993-10-08 1998-11-24 The United States Of America As Represented By The Department Of Health And Human Services Use of nitric oxide releasing compounds to protect noncancerous cells from chemotherapeutic agents
US5650442A (en) * 1993-10-08 1997-07-22 The United States Of America As Represented By The Department Of Health And Human Services Use of nitric oxide releasing compounds as hypoxic cell radiation sensitizers
US5648101A (en) * 1994-11-14 1997-07-15 Tawashi; Rashad Drug delivery of nitric oxide
US5714511A (en) * 1995-07-31 1998-02-03 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Selective prevention of organ injury in sepsis and shock using selection release of nitric oxide in vulnerable organs
US6916835B2 (en) 1996-06-04 2005-07-12 Queen's Uninversity At Kingston Nitrate esters and their use for neurological conditions
US20050137191A1 (en) * 1996-06-04 2005-06-23 Thatcher Gregory R. Nitrate esters and their use for mitigating cellular damage
US6310052B1 (en) 1996-06-04 2001-10-30 Queen's University At Kingston Nitrate esters and their use for neurological conditions
EP0951293A4 (en) * 1996-11-06 2002-06-26 Bristol Myers Squibb Co METHOD FOR TREATING ALZHEIMER DISEASE
EP0951293A1 (en) * 1996-11-06 1999-10-27 Bristol-Myers Squibb Company Method for treating alzheimer's disease
EP1050309A4 (en) * 1998-01-30 2002-10-23 Sumitomo Pharma NEUROTROPHIC FACTOR SECRETION PROMOTERS
EP1050309A1 (en) * 1998-01-30 2000-11-08 Sumitomo Pharmaceuticals Company, Limited Neurotrophic factor secretion promoters
US6451337B1 (en) 1998-11-25 2002-09-17 The University Of Akron Chitosan-based nitric oxide donor compositions
US7326730B2 (en) 2000-02-22 2008-02-05 Adamas Pharmaceuticals, Inc. Aminoadamantane derivatives as therapeutic agents
US20040110691A1 (en) * 2001-11-13 2004-06-10 Stamler Jonathan S. Thiol reactive agents as a therapeutic modality
US20080145449A1 (en) * 2001-11-13 2008-06-19 Duke University Thiol reactive agents as a therapeutic modality
EP2289489A2 (en) 2003-11-05 2011-03-02 Merz Pharma GmbH & Co. KGaA Compositions comprising cyclohexylamines and aminoadamantanes
EP2397122A2 (en) 2004-06-17 2011-12-21 Merz Pharma GmbH & Co. KGaA Formulations of neramexane dosage forms
EP2601937A1 (en) 2004-06-17 2013-06-12 Merz Pharma GmbH & Co. KGaA Drinkable immediate release tablet made with direct compression of memantine or neramexane
EP2111858A1 (en) 2008-04-25 2009-10-28 EPFL Ecole Polytechnique Fédérale de Lausanne Novel treatment for alzheimer's disease
WO2009152483A2 (en) * 2008-06-12 2009-12-17 University Of Alabama Huntsville Nitric oxide induced adaptive resistance as a therapy for central nervous system diseases and trauma
WO2009152483A3 (en) * 2008-06-12 2012-05-18 University Of Alabama Huntsville Nitric oxide induced adaptive resistance as a therapy for central nervous system diseases and trauma
WO2009152479A1 (en) * 2008-06-12 2009-12-17 University Of Alabama Huntsville Compositions comprising nitric oxide or nitric oxide donors for the treatment of neurodegenerative diseases of trauma
US8901171B2 (en) 2010-01-27 2014-12-02 Takeda Pharmaceutical Company Limited Compounds for suppressing a peripheral nerve disorder induced by an anti-cancer agent
US9616015B2 (en) 2012-05-25 2017-04-11 Diamedica Inc. Formulations of human tissue kallikrein-1 for parenteral delivery and related methods
US9364521B2 (en) 2012-06-04 2016-06-14 Diamedica Inc. Human tissue kallikrein 1 glycosylation isoforms
US9839678B2 (en) 2012-06-04 2017-12-12 Diamedica Inc. Human tissue kallikrein 1 glycosylation isoforms
US11857608B2 (en) 2017-03-09 2024-01-02 Diamedica Inc. Dosage forms of tissue kallikrein 1

Also Published As

Publication number Publication date
EP0581856A1 (en) 1994-02-09
JP2006117693A (ja) 2006-05-11
ATE182076T1 (de) 1999-07-15
EP0581856A4 (es) 1994-03-02
WO1992018112A1 (en) 1992-10-29
DE69229598D1 (de) 1999-08-19
EP0581856B1 (en) 1999-07-14
DE69229598T2 (de) 1999-11-04
JPH06506690A (ja) 1994-07-28
ES2134804T3 (es) 1999-10-16

Similar Documents

Publication Publication Date Title
US5234956A (en) Method of preventing NMDA receptor complex-mediated neuronal damage
US5455279A (en) Regimen method of mediating neuronal damage using nitroglycerine
Haley et al. The role of nitric oxide in hippocampal long-term potentiation
US5587384A (en) Inhibitors of poly(ADP-ribose) synthetase and use thereof to treat NMDA neurotoxicity
Blaise et al. Nitric oxide, cell signaling and cell death
Tieu et al. D-β-Hydroxybutyrate rescues mitochondrial respiration and mitigates features of Parkinson disease
Lirk et al. Inducible nitric oxide synthase-time for reappraisal
Medvidovic-Grubisic et al. Hypermagnesemia disturbances in rats, NO-related: pentadecapeptide BPC 157 abrogates, L-NAME and L-arginine worsen
Al-Sa'doni et al. Current status and future possibilities of nitric oxide-donor drugs: focus on S-nitrosothiols
WO2002017898A2 (en) Compositions and methods for inducing vasorelaxation
JPH06506212A (ja) Ｈｉｖウイルス系疾病、ヘルペス、色素性網膜炎およびマラリアの治療向けリボフラビンの利用
US20030100482A1 (en) NMDA oxidizing agents for protecting neurons from injury
US6071876A (en) Method of preventing NMDA receptor complex-mediated neuronal damage
CA2446074C (en) Carbonic anhydrase activators for enhancing learning and memory
Schoonover et al. Hemodynamic and cardiovascular effects of nitric oxide modulation in the therapy of septic shock
US6043268A (en) Agent for treatment of viral infections
Grobecker et al. Effect of prolonged treatment with adrenergic neuron blocking drugs on sympathoadrenal reactivity in rats
Shukla Nitric oxide in neurodegeneration
Alonso et al. Nitric-oxide-related and non-related mechanisms in the acetylcholine-evoked relaxations in cat femoral arteries
Reynolds et al. Neuroprotection against ischemic brain injury conferred by a novel nitrate ester
MXPA06000022A (es) Derivados de 2-aminobenzoilo.
US20160354330A1 (en) Treatment of levodopa-induced dyskinesias
El-Rakhawy et al. Targeting the Glutamate Amino Acid by Alpha-Ketoisocaproic Acid and L-2-Oxothiazolidine-4-Carboxylic Acid as a Neuroprotective Approach in Rat Model of Cerebral Ischemia
Childers Jr Patent Update: Cerebral Anti-lschaemic Agents: Recent Advances, June Through December, 1991
WO2000067731A2 (de) Arzneistoffverwendung zur vermeidung von nitrattoleranz

Legal Events

Date Code Title Description
STCF Information on status: patent grant

Free format text: PATENTED CASE

FEPP Fee payment procedure

Free format text: PAT HLDR NO LONGER CLAIMS SMALL ENT STAT AS INDIV INVENTOR (ORIGINAL EVENT CODE: LSM1); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

FPAY Fee payment

Year of fee payment: 4

CC Certificate of correction
FEPP Fee payment procedure

Free format text: PAYOR NUMBER ASSIGNED (ORIGINAL EVENT CODE: ASPN); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

FPAY Fee payment

Year of fee payment: 8

FPAY Fee payment

Year of fee payment: 12